In solid preparations such as tablets, pills, granules, powders, fine particles, troches, masticatories, etc. in the industries of medicines, foodstuffs, etc., additives such as excipients, stabilizers, preservatives, buffers are used in order to stabilize the active components, the shape of the preparation per se or to improve the usefulness. Such additives must be harmless in the ingestion in the above preparations and should not inhibit the effects of the active components of the preparations or not be of a hindrance to tests.
Conventional solid preparations contain various types of excipients such as starches like potato starch, corn starch, etc., sugars like lactose, sucrose, glucose, etc., inorganic salts like calcium phosphate, precipitated calcium carbonate, etc., for the purpose of diluting the active components. Soluble saccharides in particular can be widely used as excipients e.g. for troches, masticatories or sublingual tablets.
Among such saccharides, lactose is widely used as an excipient, thanks to its high stability under high humidity condition and the easy handling when making tablets. However, lactose has many problems as mentioned below.
One of the problems of lactose consists in its insufficient hardness when compressed, due to the loose binding among the crystal particles, when used as an additive as crystallized in making tablets.
Japanese Laid-Open Patent No. 6-205959 refers to granules, saying “A spherical granule comprises 95% by weight or more of lactose, and has a long diameter/short diameter ratio of 1.2 or less, and, as an assembly, a bulk density of 0.7 g/ml or more and an angle of repose of 35° or less. The spherical granule is made by feeding lactose particles into a granulating and coating apparatus equipped with a horizontal rotary disk having a smooth surface to contact with the granules, and by spraying lactose solution while the above-mentioned rotary disk is rotated”. However, tablets made of granules manufactured in this way cannot be sufficiently hard, while it takes much time to disintegrate, despite such insufficient hardness, thereby failing to be a satisfactory excipient for compressed tablets.
Japanese Laid-Open Patent No. 62-265295 refers to “Spray dried lactose products obtained by feeding a slurry of crystalline α-lactose hydrate in a saturated lactose solution to a spray drier and drying the same, in which less than 50% by weight of the lactose is in amorphous form and at least 50% by weight of the crystalline part consists of particles of 50 μm or less”. However, when used as an excipient for compressed tablets, this spray dried lactose shifts in its amorphous part to a stable crystalline state, due to compression energy when making tablets, absorbing or releasing moisture, to change the hardness of tablets greatly, thereby failing to be a satisfactory excipient for compressed tablets.
Moreover, lactose is highly reactive due to the hemiacetal structure in the molecule, to produce a brown reactant, particularly in the presence of active components having primary amino groups, by Maillard reaction resulting from reaction between carbonyl and amino groups. It is known that vitamin D3 derivatives in particular are remarkably decomposed when blended with lactose. Moreover, when the active components are acid, lactose has a disadvantage of disaccharide to be spited on hydrolysis into glucose and galactose, losing the properties of lactose, thereby failing to be a satisfactory excipient for compressed tablets also in terms of chemical stability with active components.
On the other hand, mannitol deserves mention as another saccharide equivalent to lactose in good stability under high humidity condition (high critical relative humidity). D-mannitol, a kind of hexitol, is widely used for various types of foodstuffs, medicinal bases, tablet or powder excipients, etc. thanks to its properties excellent in stability under high humidity condition, usually in the form of white crystalline powder, odor-free, mildly tasting as sweet as 60 to 70% of sucrose to have the effect of masking bitterness, less caloric than sucrose or glucose, safe to users, etc. also enabling use of highly reactive active components, unlike lactose, thanks to its chemical stability.
However, crystal particles of mannitol just having crystallized out from water are loosely bound to one another, as in the case of lactose, failing to be hard enough, when directly compressed, to keep the tablets from collapsing during transport. In addition, its fine crystalline spiculae are poor in fluidity, to cause capping, sticking, etc. when compressed, failing to enable continuous compressing.
Diverse methods for producing mannitol particles utilizable as various excipients have been proposed for the purpose of overcoming the drawbacks of crystallized mannitol as excipient for compressed tablets.
The specification of Japanese Patent No. 3447042 discloses “A process for producing a spherical particle comprising a granulated particle containing at least 95 wt % of a water-soluble single substance which has a viscosity of 10 cps or less as determined in the form of a saturated aqueous solution, the spherical particle having an aspect ratio of 1.2 or less and, as an assembly, having a bulk density of 0.65 g/ml or more and an angle of repose of 35 degree or less”, referring to D-mannitol as an example of “water-soluble single substance”.
The specification of Japanese Patent No. 3491887 discloses “a process for producing a sugar alcohol granule assembly for direct compression processing, in which 95 wt % or more of the assembly is present as particles of 710 μm or less and 50 wt % or more of the assembly as those of 75 to 710 μm, and the assembly has a bulk density of 0.5 g/ml or more and an angle of repose of 40 degree or less, the process comprising the steps of charging a powder having a sugar alcohol content of 95% by weight or more into a fluidized-bed granulating and coating apparatus; fluidizing the powder with fluidized air fed into the vessel; spraying an aqueous solution to granulate the powder; and sifting it through a sieve”, referring to D-mannitol as an example of “sugar alcohol”.
The specification of Japanese Patent No. 3910939 discloses “a spherical particle comprising an assembly of particles containing at least 95% by weight of a water-soluble single substance, the spherical particle having an aspect ratio of 1.2 or less and, as an assembly, having a bulk density of 0.65 g/ml or more, an angle of repose of 35 degree or less, wherein:
a) the single substance is one selected from the group consisting of a sugar alcohol, vitamin C and sodium chloride;
b) a saturated aqueous solution of the single substance has a viscosity of 10 cps or less at temperatures of 25 to 45° C.;
c) the spherical particle has an abrasiveness of 1.0% or less”, referring to D-mannitol as an example of “sugar alcohol”
The specification of Japanese Laid-Open Patent No. 7-184590 discloses “a process for preparing a relatively pure powdered mannitol having, a non-excessive and reduced friability of between 40 and 80% in a test I, a low apparent density of between 300 and 525 g/l for a particle size fraction (omitted) of, between 100 and 200 microns, and in addition a special particle size distribution in the sense that it contains less than 30% of particles smaller than 75 microns, the process comprising the steps of spraying a mannitol solution or suspension and granulating by wet route the mannitol obtained at the spraying step”.
The processing techniques adopted in the above four specifications are all based on granulation. Granulation here means a method of precipitating solid ingredients by agglomeration of surrounding mannitol particles around core mannitol particles, by means of appropriate solvents or solution as needed, e.g. drying the surroundings or a combined use of such methods, at any rate, in order to grow the raw material powder gradually into big agglomerations.
Needle crystals like those of mannitol, used as raw material powder, are made into heavy particles filled up with crystals densely even inside, tending to have a large particle diameter, failing to respond to the need for light and fine particles such as in the case of excipients required to have fluidity of particles.
As an example of directly compressed product made by granulation, Pearlitol is now on sale from ROQUETTE FRERES, however, still leaving room for improvement as an excipient in the insufficient hardness and high hygroscopicity of made tablets.
The specification of Japanese Laid-Open Patent No. 2004-2290 discloses “a process for the preparation of directly compressible mannitol having a content of the β modification of greater than 90%, in which a) in a first step, an aqueous D-mannitol solution as starting material, spray gas, pulverulent β-mannitol and hot gas are combined, b) the resultant pulverulent product is precipitated into a fluidized bed, taken up, fluidized and transported further”. However, the same specification makes no reference to the made particles, nor to their properties or to the tablets made with the particles.
On the other hand, crystallized mannitol (trade name: Parteck M200) made by granulation as a direct compressing excipient is now on sale from Merck, however, still leaving room for improvement as an excipient in the high hygroscopicity of tablets made of this product.
Therefore, particles of crystalline mannitol have so many problems still remaining unsolved, when used as an excipient for medicinal preparations.